E-cigarettes and related technologies offer an important potential avenue for reducing the death and disease resulting from cigarette smoking. However, relatively few controlled investigations have been conducted to assess the influence of e-cigarette contents on product use and concurrent smoking of conventional cigarettes. It is important to determine how the contents of e-cigarettes influence their use and whether the absence of constituents in e-cigarettes that are present in conventional cigarettes provides a barrier to acceptability for smokers who may have become dependent on these constituents in conventional cigarettes. Continued use of conventional cigarettes along with e-cigarettes, which currently characterizes a substantial proportion of e- cigarette use, will attenuate any harm reduction associated with switching from combustible cigarettes to e- cigarettes. Cigarette addiction critically involves a dependence on nicotine, but it is likely that other tobacco constituents contribute to dependence. Mounting evidence implicates non-nicotine tobacco alkaloids, or NNTAs (including anabasine, anatabine, nornicotine and myosmine) in tobacco dependence. These alkaloids have been shown to augment the reinforcing effects of nicotine in animal models and to affect craving in human smokers. E-cigarettes contain variable quantities of nicotine and NNTAs, but there is virtually no information available concerning the role of e-cigarette nicotine or NNTA content in influencing the concurrent use of cigarettes and e-cigarettes, when smokers attempt to make a transition from conventional combustible cigarettes to e-cigarettes. Additionally, it is not known whether the presence of nicotine and NNTAs in e- cigarettes may sustain dependence, making it difficult to relinquish these products, as well as potentially increasing their use among adolescents. The proposed study will assess the effects of e-cigarette nicotine and NNTA content on cigarette smokers who will be randomized to conditions that manipulate the nicotine and NNTA content of e-cigarettes. Dependence and concurrent use of e-cigarettes and cigarettes will be assessed by a battery of self-report, biochemical, and behavioral indices. The findings from this project will have direct application to regulatory decision-making of the FDA. In so doing, the findings will facilitate the mission of FDA to effectively curb tobacco addiction and make tobacco-related death and disease part of America's past.